SCoV2-MD: a database for the dynamics of the SARS-CoV-2 proteome and variant impact predictions.

SCoV2-MD (www.scov2-md.org) is a new online resource that systematically organizes atomistic simulations of the SARS-CoV-2 proteome. The database includes simulations produced by leading groups using molecular dynamics (MD) methods to investigate the structure-dynamics-function relationships of viral proteins. SCoV2-MD cross-references the molecular data with the pandemic evolution by tracking all available variants sequenced during the pandemic and deposited in the GISAID resource. SCoV2-MD enables the interactive analysis of the deposited trajectories through a web interface, which enables users to search by viral protein, isolate, phylogenetic attributes, or specific point mutation. Each mutation can then be analyzed interactively combining static (e.g. a variety of amino acid substitution penalties) and dynamic (time-dependent data derived from the dynamics of the local geometry) scores. Dynamic scores can be computed on the basis of nine non-covalent interaction types, including steric properties, solvent accessibility, hydrogen bonding, and other types of chemical interactions. Where available, experimental data such as antibody escape and change in binding affinities from deep mutational scanning experiments are also made available. All metrics can be combined to build predefined or custom scores to interrogate the impact of evolving variants on protein structure and function.

Structural basis of the activation of the CC chemokine receptor 5 by a chemokine agonist.

The human CC chemokine receptor 5 (CCR5) is a G protein-coupled receptor (GPCR) that plays a major role in inflammation and is involved in cancer, HIV, and COVID-19. Despite its importance as a drug target, the molecular activation mechanism of CCR5, i.e., how chemokine agonists transduce the activation signal through the receptor, is yet unknown. Here, we report the cryo-EM structure of wild-type CCR5 in an active conformation bound to the chemokine super-agonist [6P4]CCL5 and the heterotrimeric Gi protein. The structure provides the rationale for the sequence-activity relation of agonist and antagonist chemokines. The N terminus of agonist chemokines pushes onto specific structural motifs at the bottom of the orthosteric pocket that activate the canonical GPCR microswitch network. This activation mechanism differs substantially from other CC chemokine receptors that bind chemokines with shorter N termini in a shallow binding mode involving unique sequence signatures and a specialized activation mechanism.

Molecular biology of coronaviruses: an overview of virus-host interactions and pathogenesis.

Coronaviruses (CoV) are enveloped, plus-strand RNA viruses that have the largest known RNA genomes and infect birds and mammals, causing various diseases. Human coronaviruses (HCoVs) were first identified in the mid-1960s and have been known to cause enteric or respiratory infections. In the last two decades, three HCoVs have emerged, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which initiated the ongoing pandemic. SARS-CoV-2 causes a respiratory illness that presents as a mild upper respiratory disease but may result in acute respiratory distress syndrome, multi-organ failure and can be fatal, especially when underlying comorbidities are present. Children account for a low percentage of coronavirus disease 2019 (COVID-19) cases, with seemingly less severe disease. Most pediatric patients present mild or moderate symptoms or are asymptomatic. However, some cases may be severe. Therefore, SARS-CoV-2 infection and COVID-19 in pediatric patients must be studied in detail. This review describes general features of the molecular biology of CoVs and virus-host interactions that may be implicated in the pathogenesis of SARS-CoV-2.

Los coronavirus son virus envueltos de ARN de polaridad positiva, con los genomas más grandes que se conocen. Infectan aves y mamíferos, y causan una amplia variedad de enfermedades. Los coronavirus humanos se identificaron a mediados de la década de 1960 y se sabe que causan infecciones entéricas y respiratorias. En las últimas dos décadas han emergido tres coronavirus humanos pandémicos, incluido el coronavirus 2 del síndrome agudo respiratorio grave (SARS-CoV-2) que ha causado la pandemia actual. El SARS-CoV-2 produce enfermedad respiratoria que se presenta con padecimientos moderados de las vías respiratorias altas, pero puede resultar en síndrome respiratorio agudo, falla multiorgánica y muerte, en especial en casos con morbilidad subyacente. Los casos de COVID-19 en niños representan un porcentaje bajo y con síntomas menos graves de la enfermedad. La mayoría de los pacientes pediátricos son asintomáticos o presentan enfermedad leve o moderada; sin embargo, también en niños la enfermedad puede ser grave, por lo que la infección con SARS-CoV-2 y la COVID-19 en pacientes pediátricos deben estudiarse con detalle. En esta revisión se describen las características generales de la biología molecular de los coronavirus y de las interacciones virus-hospedero que se conocen para los coronavirus humanos identificados previamente, y que podrían estar implicados en la patogénesis del SARS-CoV-2.

Development of SARS-CoV-2 IgM and IgG antibodies in a relapsing multiple sclerosis patient on ofatumumab.

We report the case of a MS patient on subcutaneous ofatumumab who became infected with SARS-CoV-2 and remained asymptomatic while developing antiviral IgM and IgG antibodies. The patient was B-cell depleted with normal serum immunoglobulin levels. Anti-SARS-CoV-2 IgG antibodies remained positive three months after the initial infection. These findings suggest that a MS patient treated with ofatumumab may be able to mount an effective humoral response to SARS-CoV-2 infection and probably to COVID-19 vaccines as well. Further research will be necessary to evaluate the humoral response of MS patients on ofatumumab to SARS-CoV-2 infection and COVID-19 vaccines.

Real-world experience of ocrelizumab in multiple sclerosis in a Spanish population.

OBJECTIVE: Pivotal trial have shown that patients with multiple sclerosis (MS) receiving ocrelizumab had better outcomes. However, data on ocrelizumab in clinical practice are limited. The aim of this study was to evaluate the preliminary safety profile and effectiveness of ocrelizumab treatment for multiple sclerosis (MS) in a real-world clinical setting. METHODS: We conducted a retrospective study including consecutive patients from nine public hospitals in south-eastern Spain who received ocrelizumab after it was approved. RESULTS: A total of 228 MS patients were included (144 with relapsing-remitting MS [RRMS], 25 secondary progressive MS [SPMS], and 59 primary progressive MS [PPMS]). Median follow-up period was 12 months (range, 1-32). No evidence of disease activity (NEDA) status at year 1 was achieved in 91.2% of the relapsing MS (RMS) population, while disability progression was detected in 37.5% of the PPMS patients (median follow-up period, 19 months). The most common adverse events reported were infusion-related reactions and infections, with the most common infections being urinary tract infections followed by upper respiratory infections and COVID-19. INTERPRETATION: The preliminary results in our real-world setting show that ocrelizumab presented excellent results in suppressing disease activity with a favorable and consistent safety profile.